Antitumor agents

ABSTRACT

The invention provides compounds of formula I:  
                 
 
     wherein Y is F, Cl, Br, methyl or methoxy; and pharmaceutically acceptable salts thereof. The compounds are effective antitumor agents. The invention also provides pharmaceutical compositions comprising a compound of formula I or a salt thereof, intermediates useful for preparing a compound of formula I, and therapeutic methods comprising administering a compound of formula I or a salt thereof to a mammal in need thereof.

PPIORITY OF INVENTION

[0001] This application claims priority of invention under 35 U.S.C.§119(e) from U.S. Provisional Application Serial No. 60/309,144, filedJul. 31, 2001, which is incorporated herein by reference.

GOVERNMENT FUNDING

[0002] The invention described herein was made in part with governmentsupport under NCI-NIH Grant Number CA82341 awarded by the NationalCancer Institute. The United States Government has certain rights in theinvention.

BACKGROUND OF THE INVENTION

[0003] U.S. Pat. No. 4,629,493 discloses herbicidal compounds of thefollowing formula:

[0004] wherein A is —CH— or —N—; X is a halogen; n is 0,1, or 2; R¹ ishydrogen or a lower alkyl group; and R² is —OH, among other values. Oneof these compounds is currently sold commercially for the control ofannual and perennial grass weeds in broadleaf crops. This compound hasthe following formula:

[0005] Corbett et. al., Investigational New Drugs, 16 129-139 (1998)evaluated a series of quinoxaline compounds for activity against solidtumors in mice. The following compound (referred to as XK469) wasreported to have broad activity against transplantable mouse tumors.

[0006] The compound was also reported to have a relatively low potency,and to produce several undesirable side effects, including in vivotoxicity, e.g., paralytic ileus, GI-epithelial damage, marrow toxicity,neuromuscular toxicity and weight loss. There is currently a need foradditional antitumor agents.

SUMMARY OF THE INVENTION

[0007] The present invention provides compounds that are effectiveantitumor agents. Accordingly, there is provided a compound of theinvention which is a compound of formula I:

[0008] wherein Y is F, Cl, Br, methyl or methoxy; or a pharmaceuticallyacceptable salt thereof.

[0009] The invention also provides a therapeutic method to inhibit tumorcell growth in a mammal, comprising administering to a mammal in need ofsuch therapy, an effective amount of a compound of the invention.

[0010] The invention also provides a therapeutic method to treat cancerin a mammal, comprising administering to a mammal in need of suchtherapy, an effective amount of a compound of the invention.

[0011] The invention also provides the use of a compound of theinvention in medical therapy.

[0012] The invention also provides the use of a compound of theinvention to manufacture a medicament for the treatment of cancer in amammal.

BRIEF DESCRIPTION OF THE FIGURES

[0013]FIG. 1 shows HPLC separations of racemic compound 21b (Scheme II)and the R-enantiomer of compound 21b using Chirobiotic T250×4.6 mm, 65%H₂O, 35% CH₃OH, 20 mM NH₄NO₃ at 1 mL/min with detection at 250 nm.

DETAILED DESCRIPTION OF THE INVENTION

[0014] It will be appreciated by those skilled in the art that compoundsof the invention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine antitumor activity using thestandard tests described herein, or using other similar tests which arewell known in the art.

[0015] A specific value for Y is fluoro.

[0016] Another specific value for Y is chloro.

[0017] Another specific value for Y is bromo.

[0018] Another specific value for Y is methoxy (—OMe)

[0019] A specific group of compounds of Formula I are compounds whereinthe carbon bearing the methyl group is in the (S) configuration.

[0020] A preferred group of compounds of Formula I are compounds whereinthe carbon bearing the methyl group is in the (R) configuration.

[0021] Preferred compounds of the invention are2-[4-(7-chloroquinolin-2-yloxy)phenoxy]propanoic acid (compound 21b);2-[4-(7-bromoquinolin-2-yloxy)phenoxy]propanoic acid (compound 21c);2-[4-(7-fluoroquinolin-2-yloxy)phenoxy]propanoic acid (compound 21a) andthe pharmaceutically acceptable salts thereof (e.g., compounds 22a, 22band 22c). More preferably, the compounds of the invention are (R)2-[4-(7-chloroquinolin-2-yloxy)phenoxy]propanoic acid (compound 21b), ora pharmaceutically acceptable salt thereof (e.g., compound 22b), and (R)2-[4-(7-bromoquinolin-2-yloxy)phenoxy]propanoic acid (compound 21c), ora pharmaceutically acceptable salt thereof (e.g., compound 22c).

[0022] In cases where compounds are sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compounds assalts may be appropriate. Examples of pharmaceutically acceptable saltsare organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

[0023] Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example, calcium)salts of carboxylic acids can also be made.

[0024] The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

[0025] Thus, the present compounds may be systemically administered,e.g., orally, in combination with a pharmaceutically acceptable vehiclesuch as an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

[0026] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

[0027] The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

[0028] The pharmaceutical dosage forms suitable for injection orinfusion can include sterile aqueous solutions or dispersions or sterilepowders comprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thiomersal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

[0029] Sterile injectable solutions are prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and freeze drying techniques, which yielda powder of the active ingredient plus any additional desired ingredientpresent in the previously sterile-filtered solutions.

[0030] For topical administration, the present compounds may be appliedin pure form, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

[0031] Useful solid carriers include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include water, dimethyl sulfoxide (DMSO), alcohols orglycols or water-alcohol/glycol blends, in which the present compoundscan be dissolved or dispersed at effective levels, optionally with theaid of non-toxic surfactants. Adjuvants such as fragrances andadditional antimicrobial agents can be added to optimize the propertiesfor a given use. The resultant liquid compositions can be applied fromabsorbent pads, used to impregnate bandages and other dressings, orsprayed onto the affected area using pump-type or aerosol sprayers.

[0032] Thickeners such as synthetic polymers, fatty acids, fatty acidsalts and esters, fatty alcohols, modified celluloses or modifiedmineral materials can also be employed with liquid carriers to formspreadable pastes, gels, ointments, soaps, and the like, for applicationdirectly to the skin of the user.

[0033] Examples of useful dermatological compositions which can be usedto deliver the compounds of formula I to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

[0034] Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

[0035] The amount of the compound, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will be ultimately at the discretion of the attendantphysician or clinician.

[0036] The compound is conveniently administered in unit dosage form;for example, containing 5 to 1000 mg/m², conveniently 10 to 750 mg/m²,most conveniently, 50 to 500 mg/m² of active ingredient per unit dosageform.

[0037] The desired dose may conveniently be presented in a single doseor as divided doses administered at appropriate intervals, for example,as two, three, four or more sub-doses per day. The sub-dose itself maybe further divided, e.g., into a number of discrete loosely spacedadministrations.

[0038] The compounds of the invention are effective anti-tumor agentsand have higher potency and/or reduced toxicity as compared to XK 469.Preferably, compounds of the invention are more potent and less toxicthan (R) XK 469, and/or avoid a potential site of catabolic metabolismencountered with XK469, i.e., have a different metabolic profile thanXK469.

[0039] The present invention provides therapeutic methods of treatingcancer in a mammal, which involve administering to a mammal havingcancer an effective amount of a compound or a composition of theinvention. A mammal includes a primate, human, rodent, canine, feline,bovine, ovine, equine, swine, caprine, bovine and the like. Cancerrefers to any various type of malignant neoplasm, for example, coloncancer, breast cancer, melanoma and leukemia, and in general ischaracterized by an undesirable cellular proliferation, e.g.,unregulated growth, lack of differentiation, local tissue invasion, andmetastasis.

[0040] The ability of a compound of the invention to treat cancer may bedetermined by using assays well known to the art. For example, thedesign of treatment protocols, toxicity evaluation, data analysis,quantification of tumor cell kill, and the biological significance ofthe use of transplantable tumors screens are documented. In addition,ability of a compound to treat cancer may be determined using the Testsas described below.

[0041] In Tests A-H the following general methodologies were employed:

Tumor and Animal Maintenance

[0042] Pancreatic ductal adenocarcinoma-03, B16-melanoma, mammaryadenocarcinoma-16/C/Adr, mammary adenocarcinoma-17/Adr, colonadenocarcinoma-26, and mammary adenocarcinoma-16/C were used in thestudies.

[0043] Tumors were maintained in the mouse strain of origin C57B1/6 (forPanc03, B16), Balb/c (for Colon 26) and C₃H (for the mammary tumors).Tumors were transplanted into the appropriate F₁ hybrid (BDF1=C57B1/6female X DBA/2 male) or the strain of origin for the chemotherapytrials. Individual mouse body weights for each experiment were within 5grams, and all mice were over 17 grams at the start of therapy. The micewere supplied food and water ad libitum.

Chemotherapy of Solid Tumors

[0044] Animals were pooled, implanted subcutaneously with 30 to 60 mgtumor fragments by a 12 gauge trocar on day 0, and again pooled beforeunselective distribution to the various treatment and control groups.For early stage treatment, chemotherapy was started within 1 to 3 daysafter tumor implantation while the number of cells was relatively small(10⁷ to 10⁸ cells). For upstaged or advanced staged trials, the tumorswere allowed to grow for five or more days before treatment was started.Tumors were measured with a caliper twice weekly. Mice were sacrificedwhen their tumors reached 1500 mg. Tumor weights are estimated fromtwo-dimensional measurements:

[0045] Tumor weight (in mg)=(a×b²)/2, where a and b are the tumor lengthand width in (mm), respectively.

End Points for Assessing Antitumor Activity for Solid Tumors

[0046] The following quantitative endpoints were used to assessantitumor activity:

[0047] a), Tumor growth delay (T−C value), where T is the median time(in days) required for the treatment group tumors to reach apredetermined size (e.g., 1000 mg), and C is the median time (in days)for the control group tumors to reach the same size. Tumor-freesurvivors were are excluded from these calculations (cures are tabulatedseparately). This value is an important criterion of antitumoreffectiveness because it allows the quantification of tumor cell kill.

[0048] b) Calculation of tumor cell kill For subcutaneously (SC) growingtumors, the log₁₀ cell kill was calculated from the following formula:${{The}\quad \log_{10}\quad {cell}\quad {kill}\quad {total}\quad ({gross})} = \frac{T - {C\quad {value}\quad {in}\quad {days}}}{(3.32)({Td})}$

[0049] where T−C is the tumor growth delay as described above and Td isthe tumor volume doubling time (in days), estimated from the best fitstraight line from a log-linear growth plot of the control group tumorsin exponential growth (100 to 800 mg range). The conversion of the T−Cvalues to log₁₀ cell kill is possible because the Td of tumors regrowingpost treatment (Rx) approximates the Td values of the tumors inuntreated control mice.

[0050] The issue of conversion of tumor growth delay (T−C value) to logtumor cell kill is justified in this series because of the large numberof cures obtained with 5 of the agents studied. Cures are a clearindication of tumor cell kill (rather than stasis of tumor cellreplication).

[0051] In selected cases, both for historic in vivo evaluation data aswell as data presented here, it is of value to compare log kill numbersfrom trials of markedly different testing schedules. For this purpose,an activity table was created, and is presented below. It should benoted that an activity rating of +++ to ++++ is needed to effect partialregression (PR) or complete regression (CR) of 100 to 300 mg size massesof most transplanted solid tumors of mice. Thus, an activity rating of +or ++ would not be scored as active by usual clinical criteria. A PR isa reduction in tumor mass to less than 50% of pretreatment size. A CR isa reduction in tumor mass to below palpable size (i.e., reduction tozero detectable mass). Conversion of log₁₀ tumor cell kill to anactivity rating Duration of Rx 5 to 20 days log₁₀ kill Antitumoractivity (gross) Highly active ++++ >2.8 +++ 2.0-2.8 ++ 1.3-1.9 +0.7-1.2 − <0.7

[0052] The treatment and control groups were measured when the controlgroup tumors reach approximately 700 to 1200 mg in size (median ofgroup). The T/C value in percent is an indication of antitumoreffectiveness: A T/C=0% means no tumor growth. A T/C=100% means noantitumor activity, i.e., the treated and control tumors grew equally. AT/C equal to or less than 42% is considered significant antitumoractivity by the Drug Evaluation Branch of the Division of CancerTreatment (NCI). A T/C value <10% is considered to indicate highlysignificant antitumor activity, and is the level used by NCI to justifya clinical trial if toxicity, formulation, and certain otherrequirements are met (termed DN-2 level activity). A body weight lossnadir (mean of group) of greater than 20% or greater than 20% drugdeaths is considered to indicate an excessively toxic dosage in mostsingle course trials.

Drug Preparation for Injections in Mice

[0053] Compound 22b (sodium salt) in Tests A-H was prepared in a 1%sodium bicarbonate solution, dH₂O or phosphate buffered saline (PBS),with pH adjusted to 7.0 to 7.5 with HCl, and administered intravenously(IV) or orally (PO), at injection volumes of 0.2 ml per injection.

Test A Evaluation Against Early Stage Pancreatic Ductal Adenocarcinoma03

[0054] The pancreatic ductal adenocarcinoma 03 tumor is highly sensitiveto taxol (++++ activity rating). It is sensitive to adriamycin (+++activity rating), moderately sensitive to VP-16, cytoxan, and CisDDPt(++ activity rating), and modestly sensitive to 5-FU (+ activity).Female BDF1 mice (obtained from NCI-Raleigh) (date of birth (hereinafterD.O.B.) Mar. 27, 2000; date of arrival (hereinafter D.O.A.) Apr. 9,2000) were implanted (tumor implant date (hereinafter D.O.T.) Mar. 17,2000) with pancreatic ductal adenocarcinoma 03 tumor, divided intotreatment and control groups. The treatment group was administeredcompound 22b each day on days 3-9 IV. The results of Test A aresummarized in Table 1.

Test B Evaluation Against Early Stage B16 Melanoma

[0055] B16 melanoma is a very drug insensitive tumor when implantedsubcutaneously (SC) It is unresponsive to VP-16, vinblastine, and Ara-C(negative (−) activity rating), marginally responsive to taxol,adriamycin and camptothecin (+ or +/− activity rating), modestlyresponsive to 5-FU, cytoxan, and CisDDPt (++ activity rating). Only BCNUand other nitrosoureas are highly active (++++ activity rating).

[0056] BDF1 female mice (obtained from NCI-CRL-Ral) (D.O.B. Jan. 24,2000, D.O.A. Feb. 29, 2000). The average weight of the mice was 21.6 gm.Mice were implanted with B16 melanoma cells, passage number 138 (D.O.T.Apr. 17, 2000). Td (tumor volume doubling time) was 1 day. The mice weredivided into a control group and three experimental groups. The controlgroup (Cage #1) received no treatment.

[0057] Cage #1 reached 1000 mg in 7 days (1.0 day Td), and tumor growthwas as expected.

[0058] In Cage #2, compound 22b (racemic) was administered IV at 40mg/kg/injection, once per day on days 1-4. A total of 320 mg/kg wasadministered. This dose was toxic, producing ⅕ drug deaths (occurring onday 7). The cause of death was marrow toxicity, as evidenced by a smallspleen size. Examination of the gastrointestinal tract revealed it wasempty, indicating no food intake prior to death. This dose producedsevere weight loss (−20.8%; nadir occurred on day 7 with full recoveryon day 11). A −20% body weight loss is considered excessively toxic byN.C.I. standards. Here, administration of compound 22b (racemic) wasassociated with a slowing of nerve conduction in the mice. At doses of50 mg/kg, the toxicity was mild, but lasted for 20 minutes on day 1, andfor 8 minutes on day 4. At high dosages, e.g., 80 mg/kg, the agentproduced a substantial post injection neuromuscular toxicity lasting forover 20 minutes but resolved by two hours. This included a distinctiveparalysis of the hind legs, indicating that the toxicity was related tothe conduction velocity, since the longer the nerves, the more functionwas affected. As will be discussed later, this slowing of nerveconduction occurs with the racemic and S-enantiomer of this series. Inall cases, it is absent in the R-enantiomeric forms.

[0059] In Cage #3, compound 22b was administered IV at 50mg/kg/injection, daily on days 1-5. A total of 250 mg/kg wereadministered. At this dose, the percentage of body weight loss was −13%(nadir occurred on day 7, full recovery on day 11, for a four day hostrecovery time). This dose was active (T/C=0, 2.6 log kill, +++ activityrating).

[0060] In Cage #4, compound 22b was administered IV, at 30mg/kg/injection daily on days 1-6 for a total administration of 180mg/kg. This dose produced a −7.4% body weight loss (nadir occurred onday 5, with a full recovery on day 9). This dose was active (T/C=15.6%,1.8 log kill, ++ activity rating).

[0061] The results of Test B are summarized in Table 2.

Test C Evaluation Against Early Stage Mammary Adenocarcinoma-16/C/Adr

[0062] Early stage mammary adenocarcinoma-16/C/Adr is a p-glycoproteinnegative multidrug resistant tumor. C3H female mice were obtained fromNCI-Kingston-CRL (D.O.B. Apr. 3, 2000; D.O.A. May 16, 2000). The averageweight of the mice was 26.3 gm. Mice were implanted with early stagemammary adenocarcinoma-16/C/Adr passage number 183 and divided into acontrol group (Cage #1) and two experimental groups (Cage #2 and Cage#3) (D.O.T.=Jun. 22, 2000). The control animals (Cage #1) received notreatment. The racemic form of compound 22b (chloro analog) wasadministered to the experimental groups as follows: Group Treatmentregime Cage 42 mg/kg compound 22b; twice daily on days 1-3 and 11-13 #2with a four hour split Cage 27 mg/kg compound 22b; twice daily on days1-3 and 11-13 #3 with a four hour split

[0063] Cage #1 reached 1000 mg in 16 days (1.2 day Td), and tumor growthwas as expected.

[0064] In Cage #2, a total administration of 504 mg/kg compound 22b wasadministered by IV This treatment produced a modest neuromuscular gaitdisturbance lasting for about ten minutes post injection. The toxicitywas most evident the first two days, becoming less evident withsubsequent injections. This dose produced a −15% body weight loss (nadiroccurred on day 7, and full recovery occurred on day 12). Interestingly,the mice gained weight during the second course of treatment (days 11-13). The agent was active at this dose (T/C=0%, 2.0 log kill, +++activity rating).

[0065] In Cage #3, a total of 324 mg/kg compound 22b was administered.This dose produced an insignificant gait disturbance, and a −1.1% lossof body weight in the Cage #3 animals (nadir occurred on day 7, and fullrecovery occurred on day 8). The agent was inactive at this doseschedule (T/C=53%, 0.6 log kill). The results of Test C of aresummarized in Table 3.

Test D Evaluation of Racemic Compound 22c Against Early Stage MammaryAdenocarcinoma-17/Adr

[0066] A racemic mixture of compound 22c (bromo analog) was evaluatedagainst a multidrug-resistant mammary tumor (Maim-17/Adr).

[0067] Female C3H/HeN (MTV-neg) mice were obtained from N.C.I. Frederick(D.O.B. was Oct. 9, 2000; D.O.A. was Nov. 14, 2000). The mice weighed anaverage of 29.3 gm. Mice were implanted with Mam-17/Adr/passage-220 (ap-glycoprotein positive multidrug-resistant-tumor) (D.O.T. was Jan. 2,2001; Td=1.0 days). Compound 22c (racemic) was prepared foradministration by suspending in 5% ethanol, 1% POE-80, and 1% sodiumbicarbonate to effect solution. Then, P.B.S. was added, and the pH wasadjusted to 7 with HCl. 0.2 ml per injection was administered IV.

[0068] Cage #1 animals received no treatment. Tumor growth as expected,reaching 1000 mg on day 7 (range 7-9) (Td=1.0 days).

[0069] Animals in cage #3 were administered the racemic preparation ofcompound 22c by IV at 50 mg/kg/injection on day 1; 62.5 mg/kg on day 2;and 60 mg/kg/injection on days 3, 6, 7, 8 for a total of 352.5 mg/kg.This dose produced a modest −5.5% body wt loss. This agent caused amodest slowing of nerve conduction, lasting approximately 10 minutes atthe 60 to 62.5 mg/kg dose. The symptoms were a mild gait disturbance.This dose had impressive antitumor activity (T/C=0, 4.2 log kill, ++++activity rating). The tumors reached 1000 mg on day 21 (range 19-42). Noantitumor agent, standard or investigation has exceeded this degree ofactivity against this tumor.

[0070] Cage #4 animals were given the racemic preparation of compound22c by IV at 30 mg/kg on day 1; 37.5 mg/kg on day 2; and 36mg/kg/injection on days 3, 6, 7, 8 for a total of 211.5 mg/kg. There wasno gait disturbance at this dose. This dose was also highly active (3.0log kill). The tumors reached 1000 mg on day 17 (range 14-21).

[0071] The racemic preparation of compound 22c was found to have thesame type of neuromuscular toxicity observed in testing a racemicpreparation of compound 22b, but it was less severe (see Test B).

[0072] Results are presented in Table 4.

Test E Evaluation of the R-Enantiomer of Compound 22b and Compound 22aAgainst Early Stage Mammary Adenocarcinoma-17/Adr

[0073] The activity of the R-enantiomer of compound 22b and compound 22a(fluoro analog) were evaluated for activity against mammary tumorMam-17/Adr, which is a p-glycoprotein positivemultidrug-resistant-tumor. C3H/HeN (MTV-neg) female mice were obtainedfrom N.C.I.-Frederick (D.O.B. was Nov. 20, 2000; D.O.A. was Jan. 2,2001). The average weight of the mice was 25.9 gm. Mice were implantedwith Mam-17/Adr/passage-223 (D.O.T. was Feb. 12, 2001; Td was 1.2 days)and divided into a control and treatment groups.

[0074] A racemic preparation of compound 22a was suspended in 3%ethanol, 1% POE-80, and 0.25% sodium bicarbonate to effect solution.Then, P.B.S. was added and the pH adjusted to 7 with HCl. A volume of0.2 ml per injection was administered to animals intravenously. TheR-enantiomer of compound 22b was suspended in 3% ethanol, 1% POE-80, and0.5% sodium-bicarbonate to effect solution. Then, P.B.S. was added andthe pH was adjusted to 7 with HCl. A volume of 0.2 ml per injection wasadministered to animals intravenously.

[0075] Cage #1, the control group, received no treatment, and reached1000 mg in 9.0 days (8.5-10), (1.2 day Td). The tumor growth was asexpected.

[0076] Cage #3 was administered 36 mg/kg of racemic compound 22a by IVon day 1, and 48 mg/kg/injection qd-2-7 for a total of 324 mg/kg. Higherindividual dosages could not be given because of severe neuromusculartoxicity (slowing in nerve conduction resulting in dysfunctional legmovements, both front and rear. The dysfunction lasted for 15 minutesfor the front legs and longer for the rear legs. This dose was active(T/C=14%, 1.5 log kill, ++ activity rating). Although active, this isclearly not an improvement over compound 22b or compound 22c.

[0077] Cages #4 and #5 received lower doses of the racemic compound 22apreparation than Cage #3. These were inactive.

[0078] Cage #6 were administered an R-enantiomer of compound 22b andneuromuscular toxicity was not produced. In Test B, the racemic form ofcompound 22b produced a slowing in nerve conduction. This result impliedthat the S-enantiomer is responsible for the neuromuscular toxicity ofcompound 22b. The S-enantiomeric form was later synthesized and injectedat 80 mg/kg/injection and also at 50 mg/kg/injection, IV, both producingmarked neuromuscular toxicity. In Cage #6, the R-enantiomer of compound22b was injected IV at 83 mg/kg/injection, qd-1-4 for a total of 332mg/kg. This dose was toxic, killing all of the 5 mice (on days 7, 7, 8,9, 10). The cause of death was GI-epithelial damage producingGI-epithelial slough resulting in diarrhea. Three of the mice hadslightly enlarged food-filled stomachs, indicating gastroparesis orparalytic ileus. The spleen sizes for all of the mice were near normal,indicating that the agent did not produce much marrow toxicity in themice.

[0079] Cage #7 were administered the R-enantiomer of compound 22b by IVat 55 mg/kg/injection, qd-1-4 for a total dose of 220 mg/kg. This dosewas somewhat toxic, producing ⅕ drug deaths and a large body weight loss(−23.4% nadir day 9 and full recovery on day 14). The one death was fromGI-epithelial damage (diarrhea) complicated with marrow toxicity (smallspleen). This dose was, however, highly active (T/C=0, 3.3 log kill,++++ activity rating). The tumors reached 1000 mg on day 22 (18-23).

[0080] Cage #8 contained only one mouse, which was used for an initialtoxicity control to evaluate neuromuscular toxicity. It was injectedwith a single bolus dosage of the R-enantiomer of compound 22bpreparation at 124.5 mg/kg on day 1 only. There was no neuromusculartoxicity. The dose was modestly active and not toxic (T/C=35%, 0.8 logkill, + activity rating).

[0081] Thus, the data indicated that compound 22a was active (Cage #2).The R-enantiomer of compound 22b was devoid of the neuromusculartoxicity that occurs with the racemic form of the agent. TheS-enantiomer was made and tested and found to be responsible for theneuromuscular toxicity.

[0082] Results are presented in Table 5.

Test F Evaluation of the R-Enantiomer of Compound 22b and theR-Enantiomer of Compound 22c Against Early Staged MammaryAdenocarcinoma-16/C

[0083] In this trial, the R-enantiomers of both compound 22c andcompound 22b were compared. Each compound was completely devoid ofneuromuscular toxicity. The lethal dose-limiting toxicities are similar(GI epithelial damage).

[0084] C3H female mice were obtained from N.C.I. (D.O.B. was Jan. 22,2001; D.O.A. was Jan. 27, 2001). The mice weighed an average of 19.2 gm.Mice were implanted SC with mammary adenocarcinoma-16/C passage-170, afast growing, highly invasive, highly metastatic tumor (D.O.T. was Mar.8, 2001; Td was 1.2 days).

[0085] The R-enantiomers of both Compound 22c and Compound 22b were eachsuspended in 3% ethanol, 1% POE-80, 0.5% sodium bicarbonate (by volume)to effect solution, P.B.S. was then added and the pH adjusted to 7 withHCl. Adriamycin (ADRIA; lot number 20338c) was suspended in dH₂O toeffect solution and the pH was adjusted to 6.0. Mice were administered0.2 ml per IV injection.

[0086] Cage #1 received no treatment, and tumor growth was as expected.The tumors reached 1000 mg on day 9.5 (range 7-12) (Td=1.0 days).

[0087] Cage #2 mice were administered the R-enantiomer of compound 22cby IV at 65 mg/kg/inj qd-1-4 for a total of 260 mg/kg. No neuromusculartoxicity occurred following the injections. All the mice died 2-3 daysfollowing the last treatment from G.I. epithelial damage.

[0088] Cage #3 mice were administered R-enantiomer of compound 22c by IVat 65 mg/kg/injection every other day (once each on days 1, 3, 5, 7) fora total of 260 mg/kg. In keeping with a very rapid host recovery timefor this analog series, there were no deaths. The mice encountered a−8.3% body weight loss (nadir day 9 with full recovery day 12),indicating that the total dose on this intermittent schedule wasadequate, but not excessive. Again, there was no neuromuscular toxicitywith this dose-schedule. This dose was active (T/C=4%; 1.7 Log kill; ++activity rating).

[0089] Cage #4 mice were administered the R-enantiomer of compound 22cby IV at 40 mg/kg/injection on the same schedule as in Cage#3 (i.e., ondays 1, 3, 5, 7) for a total of 160 mg/kg. There was no toxicity and themice gained weight during treatment (+6.4% body weight gain). This dosewas also active (T/C=9%; 1.4 Log kill; and ⅕ cures; ++ activity ratingif the cure is not considered). The tumor free mouse was reimplantedwith Mam16/C tumor on day 155. The implant grew successfully, indicatingthat immunogenic factors were not involved in the original cure.

[0090] Cage #5 mice were administered the R-enantiomer of compound 22bby IV at 50 mg/kg/inj qd-1-5 for a total of 250 mg/kg. No neuromusculartoxicity occurred post injections. This dose caused an excessive weightloss, but no deaths. The mice regained all the weight within 5 days(−22.9% body weight loss on day 8, with full recovery on day 13,indicating that some of the weight loss was from dehydration). This dosewas highly active (T/C=0%; 2.1 Log kill; +++ activity rating).

[0091] Cage #6 mice were administered the R-enantiomer of compound 22bby IV at 50 mg/kg/injection on days 1, 3, 5, 7 for a total of 200 mg/kg.This dose was well tolerated, and caused no weight loss. It was active(T/C=5%; 1.7 Log kill; ++ activity rating). It is likely that a higherdose could be given on this schedule, considering the lack of weightloss.

[0092] Cage #7 mice were administered the R-enantiomer of compound 22bby IV at 30 mg/kg/injection on the same schedule as in Cage-6 for atotal of 120 mg/kg. The mice gained weight. This dose was modestlyactive (T/C=32%; 0.8 Log kill; + activity rating).

[0093] Cage #11 mice were administered adriamycin as a positive control.Historically, adriamycin is one of the most active agents against thistumor. 7.5 mg/kg/injection was administered by IV on days 1 and 5, for atotal of 15 mg/kg. While no body weight loss was observed, the mice didnot begin to re-gain weight until day 11, and then only modestly. Therewas one delayed drug-death in this group. As expected, this agent washighly active (T/C=0%; 3.6 Log kill; ++++ activity rating, although at atoxic dose).

[0094] At dosages that produced less than 10% body weight loss, theR-enantiomer of compound 22b and the R-enantiomer of compound 22c wereequally active, each with a 1.7 log kill (see Cages 3 and 6). At equalactive dosages, the R-enantiomer of compound 22b had a slightly lowerdose requirement (200 mg/kg—see Cage 6) than the R-enantiomer ofcompound 22c (260 mg/kg—see Cage 4).

[0095] Results are presented in Table 6.

Test G Evaluation of the R-enantiomers of Compounds 22c and 22b againstUp-staged Pancreatic Ductal Adenocarcinoma-03

[0096] In this trial, the R enantiomers of Compound 22c and 22b werecompared.

[0097] BDF1 female mice were obtained from N.C.I., CRL-Ral (D.O.B. wasFeb. 26, 2001; D.O.A. was Mar. 10, 2001). The mice weighed an average of22.5 gm. Mice were implanted SC with pancreatic ductal adenocarcinoma-03passage 143. (D.O.T. was May 29, 2001; Td was 2.3 days).

[0098] The R-enantiomer of compound 22c was suspended in 3% ethanol, 1%POE-80, 0.25% sodium bicarbonate (by volume) to effect solution. dH₂Owas then added, and the pH adjusted to 7 with HCl. Mice wereadministered 0.2 ml per IV injection. The R-enantiomer of compound 22bwas suspended in 3% ethanol, 1% POE-80, 0.5% sodium-bicarbonate (byvolume) to effect solution. Then, dH2O was added, and the pH adjusted to7.5 with HCl. Mice were injected with 0.2 ml per injection IV or PO.Adriamycin (source ADRIA; lot 2033BC) was suspended in dH2O to effectsolution, and the pH was 6.0. Mice were administered 0.2 ml per IVinjection.

[0099] Treatment began six days following implant, at which time thetumors were palpable size (126 mg median). The duration of treatment wasprolonged (18 days) in order to obtain a clear separation in efficacybetween the compounds.

[0100] Cage #1 received no treatment, and tumor growth was as expected.The tumors reached 1000 mg on day 16.5 (range 15-21; Td=2.3 days).

[0101] Cage #2 mice were administered compound 22b (R-enantiomer) by IVat 80 mg/kg/injection on an intermittent schedule (1×/day on days 6, 9,12, 15, 18, 21, 24) for a total of 560 mg/kg. The regimen was welltolerated with no weight loss or deaths. The mice were agitated post IVinjection, but the behavior lasted only a few minutes. There is noneuromuscular toxicity with the R-enantiomer. This dose was active (2.3log kill, {fraction (2/7)} PR's, +++ activity rating). Thisdose-schedule was clearly inferior to compound 22c (R-enantiomer).

[0102] Cage #3 mice were administered compound 22b (R-enantiomer) by IVat 50 mg/kg/inj on an intermittent schedule (1×/day on days6,9,12,15,18,21,24) for a total of 350 mg/kg. The regimen was welltolerated with no weight loss or deaths. This dose was active (1.5 logkill, ⅙ CR's, ++ activity rating).

[0103] Cage #4 mice were administered compound 22b (R-enantiomer) by IVat 31 mg/kg/inj on an intermittent schedule (1×/day on days 6, 9, 12,15, 18, 21, 24) for a total of 217 mg/kg. The regimen was well toleratedwith substantial weight gain. This dose was not active (0.5 logkill,—activity rating).

[0104] Cage #5 mice were administered compound 22b (R-enantiomer) SC at31.2 mg/kg/inj on a daily schedule (qd 6-24) for a total of 592.8 mg/kg.The regimen was well tolerated with only minor weight loss and nodeaths. The mice were not agitated post SC injection. This dose was onlymodestly active (0.9 log kill, ⅕ CR's, + activity rating). The one tumorfree mouse was reimplanted with 30 mg tumor fragments of P03 on day 157.The implant grew, indicating that immune factors were not involved inthe original cure. This SC daily schedule was clearly inferior to the IVintermittent schedule (compare to cage #2).

[0105] Cage #6 mice were administered compound 22b (R-enantiomer) SC at19.5 mg/kg/inj on a daily schedule (qd 6-24) for a total of 370.5 mg/kg.The regimen was well tolerated with no weight loss and no deaths. Themice were not agitated post SC injection. This dose was not active (0.4log kill,—activity rating). This SC daily schedule was clearly inferiorto the IV intermittent schedule (compare to cage #3).

[0106] Cage #12 mice were administered compound 22c (R-enantiomer). Onlylimited drug supply was available, thus only one dose level IV wastested, and only 4 mice per group could be used. Compound 22c wasadministered IV at 80 mg/kg/inj on an intermittent schedule (1×/day ondays 6, 9, 12, 15, 18, 21) for a total of 480 mg/kg. The day 24injection was omitted because the drug supply was exhausted. The regimenwas well tolerated with no weight loss and no deaths. The mice wereagitated post IV injection, but the behavior lasted only a few minutes.There was slightly more agitation with this compound analog thanoccurred with compound 22b. There is no neuromuscular toxicity with theR-enantiomer. This dose was highly active (3.1 log kill, ¾ completeregressions, ++++ activity rating). This dose-schedule with compound 22cwas markedly superior to compound 22b against this pancreatic ductaladenocarcinoma.

[0107] Cage #13 mice were administered adriamycin as a positive control.Historically, adriamycin is a highly active agent against this tumor. Adosage of 7.5 mg/kg/injection was given IV days 6,14 for a total of 15mg/kg (the approximate maximum tolerated dose). This was well toleratedin this trial, with no weight loss and no deaths. As expected, thisagent was active, (2.3 log kill, ⅕ CR's, +++ activity rating).

[0108] Compound 22c-R-enantiomer was markedly superior to compound 22bon an intermittent dose schedule given IV. The intermittent schedule IVwas clearly superior to the daily oral schedule.

[0109] Results are presented in Table 7.

Test H Evaluation of the R-enantiomers of XK-469, Compound 22b, andCompound 22c Against Advanced Staged Colon Carcinoma 26 in Female Balb/cMice

[0110] In this trial the R-enantiomers of XK-469, compound 22c, andcompound 22b were compared against advanced staged colon carcinoma 26 infemale Balb/c mice. Compound 22c was markedly more active than compound22b or compound XK469 against this colon carcinoma. Cage #2 was 22b at400 mg/kg and Cage 4 was 22c at 400 mg/kg. Both were toxic and omittedfrom this table.

[0111] * The “*” asterisk indicates the tumor is highly metastatic andtoxic, causing substantial body weight loss. In the treated groups, theweight loss was determined at a time before the tumor had a substantialimpact.

[0112] The XK469-R, 22b, and 22c compound doses were all prepared thesame, using 3% ethanol, 1% POE-80, and 0.5% sodium bicarbonate. Theinjection volume was 0.2 mL/mouse IV. Cytoxan was prepared in dH₂O andinjected IV in a volume of 0.2 mL per mouse. The mice were Balb/c femalemice: DOB Feb. 12, 2001; DOA Mar. 27, 2001; DOT Aug. 8, 2001, with anaverage body weight of 24.7 grams at the start of Rx administration. Thetumor was Colon Carcinoma-26 passage 141; date of implant Aug. 8, 2001,and implanted at 30 to 60 mg fragments bilaterally SC. All tumors were63 to 171 mg on day 6, the day of first Rx.

[0113] Cage #1: Control: growth as expected, 1.7 day Td.

[0114] Cage #3: 22b: 50 mg/kg/injection was given IV on days 6, 8, 10,13, and 15 for a total of 250 mg/kg. This produced ⅙ completeregressions and a 1.4 log kill (++ activity rating).

[0115] Cage #5: 22c: 50 mg/kg/injection was given IV on days 6, 8, 10,13, and 15 for a total of 250 mg/kg. This produced {fraction (3/6)}complete regressions, and {fraction (3/6)} tumor free survivors on day55. These mice remained in excellent condition, gaining weight andskeletal size. They were reimplanted with 30 mg fragments of Colon-26 onday 156. The implants grew successfully, indicating that immune factorswere not involved in the original cures (++++ activity rating).

[0116] Cage #6: XK469-R: 80 mg/kg/injection was given IV on days 6, 8,10, 14, and 16 for a total of 400 mg/kg (The historic MTD is in the 400to 450 mg/kg range). There were no regressions. This dosage produced 0.9log kill (+ activity rating).

[0117] Cage #7: XK469-R: 50 mg/kg/injection was given IV on days 6, 8,10, 13, and 15 for a total of 250 mg/kg. This dose was inactive.

[0118] Cage #8: Cytoxan was injected IV at 110 mg/kg per injection ondays 6, and 10 for a total of 220 mg/kg. There was no meaningfulactivity. Historically Cytoxan is active against this tumor if treatmentis started on day 1 (the day after implant).

[0119] The results are presented in Table 8.

[0120] The invention will now be illustrated by the followingnon-limiting examples:

EXAMPLE 1 Synthesis of[4-[(7-Substituted-2-guinolinyl)oxy]phenoxy]-propionic acids (SchemesI-III)

[0121] As shown in Scheme I, a one-pot preparation oftrans-3-ethoxyacryloyl chloride (4) by reaction of ethyl vinyl ether (2)and oxalyl chloride (3), with subsequent decarboxylation, has beendescribed by Tietze et al., Synthesis, 1079-1080 (1993). The amidationof the meta-substituted anilines (5a-e) with 4, i.e., the conversion to6a-e, was modeled after the procedure described by Campbell and Roberts(U.S. Pat. No. 4,710,507) for preparation oftrans-N-(4-bromo-3-methylphenyl)-3-ethoxypropenamide. Cyclization of thelatter to a mixture of 5-(8a-3) and 7-substituted quinolin-2-ols (7a-e)was effect in either concentrated sulfuric or hydrochloric acid(Campbell and Roberts). The mixture, in turn, was transformed to thecorresponding 2-chloroquinoline derivatives (9a-e) and (10a-e), onrefluxing with phosphorous oxychloride (Campbell and Roberts). Themajority of the 7-substituted derivatives (9a-e) separated from theregioisomer (10a-e) on fractional crystallization. The residue yieldedadditional 9a-c, following column chromatography over silica gel.

[0122] As illustrated in Scheme II, the 2-chloroqionolines 9a-e werecoupled with 2-(4-hydroxyphenoxy)propionic acid (20) using either NaH orK₂CO₃ in refluxing DMF followed by acidification to give the acids(21a-e). These acids can also be converted to their metal salts (22a-e)by reacting with metal hydroxides. XK469, which possesses a singlestereogenic center at C-2 of the propionic acid moiety, is generallyprepared in the form of a racemic mixture. The R-(+) forms of 21b and21c were prepared by etherification of commercially availableR-(+)-2-(4-hydroxyphenoxy)propionic acid with 9b and c. Chiral HPLC ofthe R-form of 21b and c, indicated that they had both been obtainedin >99% ee (see FIG. 2).

[0123] HPLC separations of racemic and R 21b were carried out usingASTEC Chirobiotic T 250×4.6 mm, 65% H₂O, 35% CH₃OH, 20 mM NH₄NO₃at 1mL/min with detection at 250 nm.

General Experimental Procedures

[0124] To a solution of the 7-substituted-2-chloroquinoline and2-(4-hydroxyphenoxy)propionic acid (1 eq) dissolved in DMF (5 mL/mmol),60% NaH (3 eq) was added in portions and the mixture heated at gentlereflux for 2 hours. After cooling it was concentrated to give a solid towhich water was added and the solution was filtered through Celite, thenwashed with water. The filtrate was extracted with ether and the aqueouslayer was acidified with 1M HCl to pH 3-4. After cooling, the solid wascollected, dried, dissolved in AcOEt and filtered through silica gel.The filtrate was concentrated to a small volume, the solid was collectedand recrystallized from AcOEt-heptane.

[0125] The reaction can also be carried out using K₂CO₃ (2.5 eq) insteadof NaH but the reaction times need to be increased to about 12 hours.

[0126] 2-[4-[(7-Fluoro-2-quinolinyl)oxy]phenoxy]propionic acid 21a (0.14g, 43% using NaH) as light yellow crystals. mp 135-137° C.; ¹H NMR (400MHz, DMSO-d₆) δ13.08 (bs, 1H), 8.38 (d, J=8.8 Hz, 1H), 7.99 (dd, II=8.8,6.4 Hz, 1H), 7.40-7.32 (m, 2H), 7.18 (d, J=8.8 Hz, 1H), 7.17-7.12 (m,2H), 6.94-6.89 (m, 2H), 4.82 (q, J=6.8 Hz, 1H), 1.51 (d, J=6.4 Hz, 3H).¹³C NMR (75 MHz, DMSO-d₆) d 173.9, 163.6 (d, J=245.5 Hz), 163.2, 155.2,147.6 (d, J=12.7 Hz), 147.3, 141.0, 130.8 (d, J=10.4 Hz), 123.4, 123.2,116.1, 115.1, (d, J=24.5 Hz), 112.71, 111.7 (d, J=20.8 Hz), 72.5, 19.0.¹⁹F NMR (376 MHz, DMSO-d₆) δ76.33 (m). MS (EI) m/z (%) 327 (M⁺, 59), 282(15), 268 (15), 254 (67), 238 (8), 226 (4), 209 (4), 198 (3), 151 (5),146 (100), 126 (12), 119 (7), 91 (7). HRMS (EI) m/z 327.0910 (M⁺, Calcdfor C₁₈H₁₄NFO₄ 327.0907).

[0127] 2-[4-[(7-Chloro-2-quinolinyl)oxy]phenoxy]propionic acid 21b (84%using K₂CO₃) as white crystals. mp 149-150° C.; ¹H NMR (400 MHz,DMSO-d₆) δ3.05 (bs, 1H), 8.40 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H),7.66 (d, J=2.8 Hz, 1H), 7.48 (dd, J=8.8, 2.4 Hz, 1H), 7.24 (d, J=8.0 Hz,1H), 7.18-7.13 (m, 2H), 6.94-6.89 (m, 2H), 4.82 (q, J=6.4 Hz, 1H), 1.51(d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d₆) δ173.6, 162.8, 155.0,147.1, 146.6, 140.6, 135.0, 129.9, 126.1, 125.6, 124.3, 123.0, 116.0,113.5, 72.4, 18.7. MS (EI) m/z (%) 343 (M⁺, 46), 298 (15), 284(16), 270(71), 254 (8), 236 (6), 167 (19), 162 (100), 155 (8), 127 (22), 114(10), 97 (11), 91 (24), 83 (16), 81 (12), 73 (19), 71 (14), 69 (23), 67(12), 63 (12), 60 (17), 57 (27), 55 (35), 45 (18). HRMS (EI) m/z343.0609 (M⁺, Calcd for C₁₈H₁₄NClO₄ 343.0611). Anal. Calcd forC₁₈H₁₄NClO₄: C, 62.89; H, 4.10; N, 4.08. Found: C, 63.00; H, 4.18; N,4.12.

[0128] R-(+)-2-[4-[(7-Chloro-2-guinolinyl)oxy]phenoxy]propionic acid wasprepared from commercially available R-(+)-2-(4-hydroxyphenoxy)propionicacid. The product was identical in all respects with the racemicproduct, and exhibited an optical rotation of [α]²⁵+19° C. 0.5, 0.1NNaOH).

[0129] 2-[4-[(7-Bromo-2-guinolinyl)oxy]phenoxy]propionic acid 21c (0.69g, 70% using NaH) as white crystals. mp 160-161° C.; ¹H NMR (400 MHz,DMSO-d₆) δ13.09 (bs, 1H), 8.39 (d, J=8.8 Hz, 1H), 7.88 (d, J=9.2 Hz,1H), 7.80 (d, J=1.6 Hz, 1H), 7.60 (dd, J=9.2, 1.6 Hz, 1H), 7.25 (d,J=8.8 Hz, 1H), 7.18-7.13 (m, 2H), 6.94-6.89 (m, 2H), 4.82 (q, J=6.8 Hz,1H), 1.51 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d₆) δ173.9, 163.0,155.3, 147.2, 147.1, 141.0, 130.3, 129.6, 128.5, 124.9, 124.0, 123.3,116.1, 114.0, 72.5,19.1. MS (EI) m/z (%) 387(M⁺, 42), 342(10), 328 (10),314 (31), 300 (6), 285 (7), 256 (22), 236 (13), 206 (53), 199 (18), 185(10), 171 (8), 157 (8), 127 (44),115 (15), 111(13), 97 (27), 91 (28), 83(33), 73 (57), 69 (45), 60 (58), 57 (56), 55 (69), 43 (100), 41 (66).HRMS (EI) m/z 387.0107 (M⁺, Calcd for C₁₈H₁₄NBrO₄ 387.0106). Anal. Calcdfor C₁₈H₁₄NBrO₄: C, 55.69; H, 3.63; N, 3.61. Found: C, 55.52; H, 3.89;N, 3.56.

[0130] R-(+)-2-[4-[(7-Bromo-2-guinolinyl)oxy]phenoxy]propionic acid wasprepared from commercially available R-(+)-2-(4-hydroxyphenoxy)propionicacid. The product was identical in all respects with the racemicproduct, and exhibited an optical rotation of [α]²⁵+22.0° C. 0.5, 0.1NNaOH).

[0131] 2-[4-[(7-Methyl-2-guinolinyl)oxy]phenoxy]propionic acid 21d (32%yield from Na) as light yellow crystals. mp 183-185° C.; ¹H NMR (400MHz, DMSO-d₆) δ13.03 (bs, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.43 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.16-7.10 (m, 3H),6.93-6.89 (m, 2H), 4.82 (q, J=6.4 Hz, 1H), 2.41 (s, 3H), 1.51 (d,J=6.4Hz, 3H). ¹³CNMR (100 MHz, DMSO-d₆) δ173.9, 162.4, 155.1, 147.6, 146.6,140.6 (2C), 128.0, 127.4, 127.0, 124.0, 123.4, 116.1, 112.3, 72.5, 21.9,19.1. MS (EI) mz (%) 323 (M⁺, 57), 305 (6), 278 (9), 276 (7), 264 (13),250 (60), 236 (10), 234 (6), 222 (5), 142 (100), 115 (17), 105 (6), 77(6). HRMS (EI) m/z 323.1164 (M⁺, Calcd for C₁₉H₁₇NO₄ 323.1158).

[0132] 2-[4-[(7-Methoxy-2-guinolinyl)oxy]phenoxy]propionic acid 21e (66%yield from K₂CO₃) as light yellow crystals. mp 164-166 C; ¹H NMR (400MHz, DMSO-d₆) δ13.06 (bs, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.8Hz, 1H), 7.16-7.10 (m, 2H), 7.06 (dd, J=8.8,2.4 Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.94-6.88 (m, 2H), 4.82 (q, J=6.4 Hz,1H), 3.81 (s, 3H), 1.51 (d, J=7.2 Hz, 3H). ¹³ C NMR (100 MHz, DMSO-d₆)δ174.0, 162.9, 161.5, 155.1, 148.3, 147.7, 140.5, 129.5, 123.4, 120.9,117.5, 116.1, 110.5, 107.0, 72.5, 56.1, 19.1. MS (EI) mz (%) 339 (M⁺,62), 323 (10), 294 (8), 280 (13), 266 (35), 250 (13), 175 (7), 158(100), 142 (18), 115 (10), 77 (6). HRMS (EI) m/z 339.1105 (M⁺, Calcd forC₁₉H₁₇NO₅ 339.1107).

EXAMPLE 2

[0133] The following illustrates representative pharmaceutical dosageforms, containing a compound of formula I (‘Compound X’), fortherapeutic or prophylactic use in humans. (i) Tablet 1 mg/tablet‘Compound X’ 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 (ii) Tablet2 mg/tablet ‘Compound X’ 20.0 Microcrystalline cellulose 410.0 Starch50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii)Capsule mg/capsule ‘Compound X’ 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0(iv) Injection 1 (1 mg/ml) mg/ml ‘Compound X’ (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5)q.s. Water for injection q.s. ad 1 mL (v) Injection 2 (10 mg/ml) mg/ml‘Compound X’ (free acid form) 10.0 Monobasic sodium phosphate 0.3Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 01 N Sodiumhydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injectionq.s. ad 1 mL (vi) Aerosol mg/can ‘Compound X’ 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0

[0134] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art.

[0135] All publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention. TABLE 1 Evaluation AgainstEarly Stage Pancreatic Ductal Adenocarcinoma 03. Total % Body MedianTumor Growth Tumor Drug # of dose Wt Loss Day of Drug Mass on Day 14 %T/C Delay in Log Free Activity Cage # IV Inj. mg/kg at Nadir NadirDeaths (Range) mass Days Kill day-37 Rating 1 None 0 0  +12% 10 — 1513(681-2149) — — — 0/5 − 7 22b 7 336 −8.9% 11 0/5   0 (0-126) 0% 17.5 2.60/5 +++

[0136] TABLE 2 Evaluation Against Early Stage B16 Melanoma. Total % BodyMedian Tumor Growth Tumor # of dose Wt Loss Day of Drug Mass on Day 9 %T/C Delay in Log Free Activity Cage # Drug Inj. mg/kg at Nadir NadirDeaths (Range) mass Days Kill day-24 Rating 1 None 0 0  +7.4% 8 — 1415(648-2224) — — — 0/5 − 2 22b 8 320 −20.8% 7 1/5   0 (all zeros)   0%12.5 3.8 0.5 ++++ Toxic 3 22b 5 250 −13.2% 8 0/5   0 (all zeros)   0%8.5 2.6 0/5 +++ 4 22b 6 180  −7.4% 5 0/5  221 (63-334) 15.6% 6.0 1.8 0/5++

[0137] TABLE 3 Evaluation Against Early Stage MammaryAdenocarcinoma-16/C/Adr. Total % Body Median Tumor Growth Tumor Drug #of dose Wt Loss Day of Drug Mass on Day 11 % T/C Delay in Log FreeActivity Cage # IV Inj. mg/kg at Nadir Nadir Deaths (Range) mass DaysKill day-18 Rating 1 None 0 0  −2.7% 7 — 1410 (447-3052) — — — 0/6 − 222b 12 504 −15.0% 7 0/6   0 (0-308)  0% 8.0 2.0 0/6 +++ 3 22b 12 324 −1.1% 7 0/6  741 (516-1199) 53% 2.25 0.6 0/6 −

[0138] TABLE 4 Evaluation of Racemic Compound 22c Against Early StageMammary Adenocarcinoma-17/Adr in Female C3H Mice Total % Body MedianTumor Growth Tumor Drug # of dose Wt Loss Day of Drug Mass on Day 10 %T/C Delay in Log Free Activity Cage # IV Inj. mg/kg at Nadir NadirDeaths (Range) mass Days Kill day-42 Rating 1 No Rx 0 0 +1.4%  9 — 3044(2385-3402) — — — 0/5 − 3 Racemic 6 352.5 −5.5% 11 0/5   0 (0-63)   0%14 4.2 0/5 ++++ 22c 4 Racemic 6 211.5 −4.1% 13 0/5  172 (0-344) 5.6% 103.0 0/5 ++++ 22c

[0139] TABLE 5 Evaluation of the R-Enantiomer of Compound 22b andCompound 22a Against Early Stage Mammary Adenocarcinoma-17/Adr in FemaleC3H Mice Total % Body Median Tumor Growth Tumor Drug # of dose Wt LossDay of Drug Mass on Day 9 % T/C Delay in Log Free Activity Cage # IVInj. mg/kg at Nadir Nadir Deaths (Range) mass Days Kill day-23 Rating 1No Rx 0 0  −2.3% 6 — 960 (828-1357) — — — 0/5 − 3 22a 7 324  −1.6% 5 0/5138 (63-207)    14% 5 1.5 0/5 ++ 4 22a 7 162  −1.5% 5 0/5 975(252-1836) >100% 1 0.3 0/5 − 5 22a 7 81  −3.0% 5 0/5 743 (725-1413)   77% 1 0.3 0/5 − 6 R-22b 4 332 −17.5% 6 5/5 toxic toxic — — 0/5 toxic7 R-22b 4 220 −23.4% 9 1/5  0 (all zeros)    0% 13  3.3 0/5 ++++ 8 R-22b1 124.5 0 9 0/1 340 (one mouse)    35% 3 0.8 0/1 +

[0140] TABLE 6 Evaluation of the R-enantiomer of Compound 22b and theR-enantiomer of compound 22c Against Early Staged MammaryAdenocarcinoma-16/C Median Median Tumor time for Tumor Schedule Total %Body Drug Mass on % tumors to Growth Free Cage days dose Wt Loss Day ofDeaths Day 10 T/C 1000 mg Delay Log day- Activity # Drug IV injectedmg/kg at Nadir Nadir (days) (Range) mass (range) in Days Kill 155 Rating1 No Rx — 0 +10.4%  8 — 1533 — 9.5 — — 0/5 — (334-3043) (7-12) 2 R-22cqd 1-4 260 −22.9%  6 5/5 toxic toxic toxic toxic toxic 0/5 toxic (6, 6,7, 7, 7) 3 R-22c 1, 3, 5, 7 260 −8.3% 9 0/5 63 (0-75) 4% 15.3 (14-21.5)5.8 1.7 0/5 ++ 4 R-22c 1, 3, 5, 7 160 +6.4%  8 0/5 138 9% 14.2(12.5-16.7) 4.7 1.4 1/5 ++ (0-396) 5 R-22b qd-1-5 250 −22.9%  8 0/5 0(0-138) 0% 16.5 (13.5-18) 7.0 2.1 0/5 +++ 6 R-22b 1, 3, 5, 7 200  0% 80/5 75 5% 15.3 (14-17) 5.8 1.7 0/5 ++ (0-171) 7 R-22b 1, 3, 5, 7 120+6.1%  8 0/5 486 32% 12 (11.5-14) 2.5 0.8 0/5 + (63-509) 11 Adriamycin1, 5 15  0% 8 1/5 0 0% 21.5 (17-27.5) 12.0 3.6 0/5 ++++ (60) (all zeros)toxic

[0141] TABLE 7 Evaluation of the R-enantiomers of Compound 22c and 22bAgainst Up-Staged Pancreatic Ductal Adenocarcinoma-03 in Female BDF1Mice % Body Median Schedule Wt change Tumor Median time days Totalbetween Drug Mass on for tumors to Growth Tumor Cg injected dose day 6and Deaths Day 24 % T/C 1,000 mg Delay in Log Free Activity # Drug(route) mg/kg day 24 (days) (Range) mass (range) Days Kill PR's CR'sday-157 Rating 1 No Rx — 0 +14.1% — 2259 (1500- — 16.5 (15-21) — — 0/60/6 0/6 — 3919) 2 R-22b 6, 9, 12, 560 +3.7% 0/7 320 (183- 14.1% 34(26-36) 17.5 2.3 2/7 0/7 0/7 +++ 15, 18, 21, 523) 24 (IV) 3 R-22b 6, 9,12, 350 +8.8% 0/6 658 (235- 29.1% 28 (23-34) 11.5 1.5 1/6 1/6 0/6 ++ 15,18, 21, 867) 24 (IV) 4 R-22b 6, 9, 12, 217 +10.4% 0/6 1722 (905- 76.2%20 (16-24.5) 3.5 0.5 0/6 0/6 0/6 − 15, 18, 21, 2355) 24 (IV) 5 R-22b 6,9, 12, 592.8 +3.5% 0/5 1105 (0- 48.9% 23 (23 − >43) 6.5 0.9 1/5 1/51/5 + 15, 18, 21, 1323) 24 (IV) 12 R-22b 6, 9, 12, 370.5 +10.3% 0/5 1868(0- 82.7% 19.5 3.0 0.4 0/5 0/5 0/5 − 15, 18, 21, 2148 (17.5 − >43) 24(IV) 13 R-22c 6, 9, 12, 480 +5.9% 0/4 63 (0-196) 2.8% 40 23.5 3.1 3/43/4 0/4 ++++ 15, 18, 21 (35.5 − >43) 24 (IV) 8 Adria- 6, 14 15 +5.4% 0/5383 (189- 17.0% 34 (28−35) 17.5 2.3 1/5 1/5 0/5 +++ mycin 400)

[0142] TABLE 8 Evaluation of the R-enantiomer of XK-469 with theR-enantiomers of Compound 22c and Compound 22b Against Advanced StagedColon Carcinoma 26 in Female Balb/c Mice Schedule days % Body Wt Mediantime injected Total change at for tumors to Growth Tumor (all IV dosenadir Drug 700 mg Delay Log Free Activity Cg # Rx route) mg/kg (day ofnadir) Deaths (range) in Days Kill PR's CR's day-156 Rating 1 No Rx — 0 −9.0% (11)* — 13 (11.5-16.5) — — 0/6 0/6 0/6 − 3 22b(R) 6, 8, 10, 13,15 250 −6.2% (16) 0/6 21 (15.5-48) 8 1.4 1/6 1/6 0/6 ++ 5 22c(R) 6, 8,10, 13, 15 250 −8.1% (17) 0/6 3/6 tumor free 3/6 >3.5 3/6 3/6 3/6 ++++tumor free 6 XK469-R 6, 8, 10, 14, 16 400 −8.1% (13) 0/6 18 (15-20) 50.9 0/6 0/6 0/6 + 7 XK469-R 6, 8, 10, 13, 15 250 −4.0% (13) 0/6 13(11.5-20) none none 0/6 0/6 0/6 − 8 Cytoxan 6, 10 220 −9.4% (12) 0/5 14(12-15) 1 0.2 0/5 0/5 0/5 −

What is claimed is:
 1. A compound of formula I:

wherein Y is F, Cl, Br, methyl or methoxy; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein Y is F. 3.The compound of claim 1, wherein Y is Cl.
 4. The compound of claim 1,wherein Y is Br.
 5. The compound of claim 1, wherein Y is —OMe.
 6. Thecompound of claim 1, wherein Y is methyl.
 7. The compound of claim 1,wherein the carbon bearing the methyl group is in the (R) configuration.8. The compound of claim 1, wherein the carbon bearing the methyl groupis in the (S) configuration.
 9. A compound of claim 1 which is2-[4-(7-chloroquinolin-2-yloxy)phenoxy]propanoic acid.
 10. A compound ofclaim 1 which is (R) 2-[4-(7-chloroquinolin-2-yloxy)phenoxy]propanoicacid.
 11. A composition comprising a compound of claim 1, in combinationwith a pharmaceutically acceptable diluent or carrier.
 12. A therapeuticmethod to treat cancer in a mammal, comprising administering to a mammalin need of such therapy an effective amount of a compound of claim 1.